Controlling Interareal Gamma Coherence by Optogenetics, Pharmacology and Behavior

描述(申请人提供)：大脑皮层区域之间的连贯性与包括注意力和工作记忆在内的认知功能有关。连贯性可能会动态地改变信息通过大脑的路径，从而提供认知所需的灵活性。事实上，连贯性障碍与精神分裂症和自闭症谱系障碍等神经障碍有关。目前还没有关于大脑皮层间连贯性如何产生的系统的活体研究。在这里，我们将测试假设，当源区域中的局部振荡传播到目标区域并与目标区域同步时，区域间皮质伽马(30-80赫兹)相干发生。计算模型预测，目标中预先存在的伽马的强度将影响其与即将到来的振荡的一致性：“弱”局部伽马振荡将很容易夹带，导致两个区域之间的一致性，而“强”振荡抵抗外部输入，使一致性变得困难(除非输入在相位和频率上匹配)。验证这一假说需要在体内对局部振荡进行因果控制，这是摩尔实验室最近利用光遗传学开发的一项技术。将光遗传学与多区域记录相结合，将使我们能够发现区域之间的振荡如何结合的规律。我们将在源区(初级体感皮质，SI)光遗传诱导局部伽马振荡，并测量它们与目标区(次级体感皮质，SII)的一致性。我们将通过三种方式操纵目标中正在进行的伽马振荡的强度来检验我们的假设。在目标1中，我们将在目标中光遗传诱导伽马振荡，参数地改变功率和相位，以确定它们对相干性的影响。胆碱能激动剂在新皮质诱导伽玛振荡，而乙酰胆碱可能是注意中观察到的区域间一致性的基础。因此，在目标2中，我们将通过增加局部胆碱能音调并测量其对一致性的影响来在靶体内诱导伽玛振荡。啮齿动物、猴子和人类的数据将伽马振荡与注意力联系在一起。因此，在目标3中，我们将测试注意力对光遗传诱导局部伽马能力的影响，以及它对建立区域间一致性的影响。这些目标将直接检验关于区域间一致性机制的一个重要假说。此外，这项提议将使我能够在克里斯托弗·摩尔博士的指导下，在小鼠身上学习光遗传学、电生理学和行为技术。我未来的职业目标是将我以前的灵长类动物经验与这些在老鼠身上的新技术结合起来。我将使用灵长类动物的电生理学，训练它们执行复杂的行为，以产生关于认知基础的神经机制的假设。这些被提出的神经机制随后可以用在老鼠身上可用的强大方法来剖析。 与公共健康相关：该项目将调查大脑区域如何在伽马振荡频段实现彼此的一致性。一致性被认为有助于大脑区域之间的交流，伽马表达和区域间一致性的变化在几种精神和大脑疾病中被发现，包括精神分裂症和自闭症。因此，我们的工作可能会提供对这些不适应变化的洞察。

DESCRIPTION (provided by applicant): Coherence between cortical regions has been implicated in cognitive functions including attention and working memory. Coherence may act to dynamically alter the routing of information through the brain, providing the flexibility that is necessary for cognition. Indeed, disruptions in coherence are linked to neural disorders such as schizophrenia and autism spectrum disorder. There has been no systematic, in vivo, study of how inter-cortical coherence arises. Here we will test the hypothesis that inter-area cortical gamma (30-80 Hz) coherence occurs when local oscillations in a source region propagate to, and synchronize with, a target region. Computational modeling predicts that the strength of pre-existing gamma in the target will affect its coherence with an incoming oscillation: 'weak' local gamma oscillations will be easily entrained, leading to coherence between the two regions, while 'strong' oscillations resist external input, making coherence difficult (unless the input matches in phase and frequency). Testing this hypothesis requires causal in vivo control of local oscillations, a technique that the Moore laboratory has recently developed utilizing optogenetics. Coupling optogenetics with multi-area recording will allow us to discover the rules of how oscillations cohere between areas. We will optogenetically induce local gamma oscillations in a source area (primary somatosensory cortex, SI) and measure their coherence with a target area (secondary somatosensory cortex, SII). We will test our hypothesis by manipulating the strength of ongoing gamma oscillations in the target in three ways. In Aim 1, we will optogenetically induce gamma oscillations in the target, parametrically varying the power and phase, in order to determine their effect on coherence. Cholinergic agonists induce gamma oscillations in the neocortex and acetylcholine may underlie the inter-areal coherence observed in attention. Therefore, in Aim 2, we will induce gamma oscillations in the target by increasing the local cholinergic tone and measuring its impact on coherence. Rodent, monkey and human data link gamma oscillations with attention. So, in Aim 3, we will test the impact of attention on the ability to optogenetically induce local gamma, and its impact on establishing coherence between areas. These aims will directly test an important hypothesis about the mechanism of inter-areal coherence. In addition, this proposal will allow me to learn optogenetic, electrophysiological, and behavioral techniques in mice, under the mentorship of Dr. Christopher Moore. My future career goals are to combine my previous primate experience with these new techniques in mice. I will use electrophysiology in primates trained to perform complex behaviors to generate hypotheses about the neural mechanisms underlying cognition. These proposed neural mechanisms can then be dissected using the powerful methods available in mice. PUBLIC HEALTH RELEVANCE: This project will investigate how brain regions achieve coherence with one another in the gamma oscillation band. Coherence is thought to aid in the communication between brain regions, and alterations in gamma expression and in inter-areal coherence are found in several mental and brain disorders, including schizophrenia and autism. Our work may, therefore, provide insight into these maladaptive changes.